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Transient receptor potential channel

Transient receptor potential (TRP) channels constitute a superfamily of cation-permeable ion channels that serve as multimodal cellular sensors, responding to diverse physical and chemical stimuli such as temperature, mechanical stress, osmolarity, and ligands.^[1] These channels primarily facilitate the influx of calcium (Ca²⁺) and sodium (Na⁺) ions, thereby regulating key cellular processes including sensory transduction, homeostasis, and signaling pathways.^[1] Expressed across nearly all cell types and tissues in mammals, TRP channels play essential roles in physiological functions ranging from pain perception and thermoregulation to cardiovascular regulation and immune responses.^[2] The discovery of TRP channels traces back to 1969, when a mutation in the trp gene in Drosophila melanogaster was found to cause a transient rather than sustained response in photoreceptor cells to light, leading to their naming as "transient receptor potential" channels in 1975.^[1] The first mammalian TRP channel, TRPC1, was cloned in 1995, and subsequent research unified the family into six mammalian subfamilies comprising 28 members: TRPC (1–7), TRPV (1–6), TRPM (1–8), TRPA (1), TRPML (1–3), and TRPP (2, 3, 5). A seventh subfamily, TRPN, is absent in mammals but present in other organisms.^[1] Structurally, TRP channels are tetrameric proteins, each subunit featuring six transmembrane domains (S1–S6) with a pore loop between S5 and S6, intracellular N- and C-termini, and varying additional domains like ankyrin repeats in TRPA and TRPV subfamilies.^[2] Functionally, TRP channels are activated by a broad spectrum of stimuli, enabling them to mediate sensory responses such as nociception (e.g., TRPV1 for heat and capsaicin-induced pain, TRPM8 for cold), mechanosensation (e.g., TRPP2 in kidney function), and taste perception.^[1] They are critical in Ca²⁺ signaling, influencing processes like inflammation, neuronal excitability, and cell proliferation, with dysregulation implicated in various pathologies including chronic pain, inflammatory bowel disease, polycystic kidney disease, and neurodegenerative disorders.^[2] Due to their therapeutic potential, TRP channel modulators—particularly antagonists for TRPV1 and TRPA1—have advanced to clinical trials for conditions like osteoarthritis pain and respiratory diseases, though challenges such as off-target effects persist.^[1]

Overview

Definition and Properties

Transient receptor potential (TRP) channels constitute a superfamily of cation-permeable ion channels that function as key mediators in cellular signaling and sensory transduction.^[3] Each channel is formed by tetrameric assemblies of subunits, where individual subunits typically feature six transmembrane domains (S1–S6) with a pore-forming loop located between S5 and S6, and intracellular N- and C-termini.^[4] These channels are expressed across a wide array of tissues, including neurons, epithelial cells, and smooth muscle, enabling their involvement in diverse physiological processes.^[1] TRP channels exhibit non-selective cation conductance, primarily permitting the influx of Ca²⁺ and Na⁺ ions, though selectivity varies among subtypes.^[3] They are characterized by polymodal activation, responding to multiple stimuli such as temperature changes, chemical ligands, mechanical stress, and osmotic pressure, which allows them to integrate a broad spectrum of environmental and intracellular signals.^[1] This versatility underpins their critical role in signal transduction pathways and sensory physiology, including nociception, thermosensation, and mechanosensation.^[4] The distribution of TRP channels is ubiquitous, spanning mammals and other organisms from yeast to vertebrates, with tissue-specific isoforms that adapt to localized functional demands.^[4] Often described as "cellular sensors," TRP channels detect and transduce physical and chemical cues into electrical and calcium signals, thereby linking external stimuli to intracellular responses.^[3] In mammals, they are subdivided into several subfamilies, each contributing to specialized sensory functions.^[1]

Discovery and Historical Development

The discovery of transient receptor potential (TRP) channels originated from studies on phototransduction in the fruit fly Drosophila melanogaster. In 1969, researchers identified a visual mutant strain exhibiting an abnormal electroretinogram, characterized by a transient receptor potential—a brief depolarization in response to light—rather than the sustained response seen in wild-type flies. This phenomenon, termed "transient receptor potential" (trp), was first described by Cosens and Manning as a light-activated conductance decrease in Drosophila photoreceptors, marking the initial observation of what would later be recognized as a novel class of ion channels.^[1] Pioneering genetic screens in Drosophila, building on the foundational work of Seymour Benzer in the 1960s and 1970s who established behavioral assays for visual mutants, facilitated the isolation of the trp locus. Key experiments in phototransduction, including electrophysiological recordings from mutant photoreceptors, revealed that the trp gene encoded a protein essential for maintaining calcium influx during prolonged light exposure. In 1989, Craig Montell and Gerald Rubin cloned the trp gene using positional cloning techniques, identifying it as a putative integral membrane protein with multiple transmembrane domains, thus providing the first molecular insight into this light-activated channel. Concurrently, Charles Zuker's laboratory contributed to understanding the TRP family's role in invertebrate vision through studies on related mutants like trpl, a TRP homolog.^[5] The 1990s saw the extension of TRP research to vertebrates, linking insect phototransduction mechanisms to mammalian sensory processes. In 1995, the first mammalian TRP homolog, TRPC1, was cloned independently by two groups based on sequence similarity to Drosophila TRP, revealing its expression in various tissues and potential role in store-operated calcium entry. This discovery spurred the identification of additional mammalian homologs, expanding the TRP family beyond visual transduction. By the early 2000s, the understanding evolved significantly with the 2002 classification of TRP subfamilies in a unified nomenclature, which resolved the vanilloid receptor VR1—previously cloned in 1997 as the capsaicin and heat-activated channel—as TRPV1, highlighting its broader sensory functions in pain and thermosensation. These milestones shifted the perception of TRP channels from specialized visual components to versatile sensors in diverse physiological contexts.00554-Y)00448-3)

Classification

Mammalian Subfamilies

In mammals, transient receptor potential (TRP) channels are encoded by 28 genes that are classified into six subfamilies based on amino acid sequence homology, typically ranging from 20% to 30% across the family, with higher similarity (around 35-40%) within subfamilies.^[4]^[1] These subfamilies—TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPP (polycystin), and TRPML (mucolipin)—reflect evolutionary divergence from ancestral channels, with the TRPC subfamily showing the closest relation to the original TRP channel identified in Drosophila melanogaster.^[3]^[4] The genes exhibit tissue-specific expression patterns, contributing to diverse physiological roles, though individual subfamily members often show overlapping yet specialized distributions across excitable and non-excitable cells.^[1] The TRPC subfamily comprises seven members (TRPC1–7), named for their sequence similarity to the Drosophila TRP protein; TRPC2 is a pseudogene in humans. These genes are located on various chromosomes, as detailed below. The TRPV subfamily includes six members (TRPV1–6), originally identified through homology to the vanilloid receptor, and are clustered on chromosomes 7 and 17 for several members. The TRPM subfamily, the largest with eight members (TRPM1–8), derives its name from the melastatin melanoma antigen (TRPM1) and spans multiple chromosomes. The TRPA subfamily has a single member, TRPA1, distinguished by its ankyrin repeat-rich structure. The TRPP subfamily consists of three members (PKD2/TRPP2, PKD2L1/TRPP3, PKD2L2), linked to polycystin proteins involved in renal function. Finally, the TRPML subfamily has three members (MCOLN1–3), associated with mucolipidosis disorders.

Subfamily	Members (Gene Symbols)	Chromosomal Locations
TRPC (Canonical)	TRPC1, TRPC3–7 (TRPC2 pseudogene)	3q23 (TRPC1), 4q27 (TRPC3), 13q13.3 (TRPC4), Xq23 (TRPC5), 11q22.1 (TRPC6), 5q31.1 (TRPC7)
TRPV (Vanilloid)	TRPV1–6	17p13.2 (TRPV1, TRPV3), 17p11.2 (TRPV2), 12q24.11 (TRPV4), 7q34 (TRPV5, TRPV6)
TRPM (Melastatin)	TRPM1–8	15q13.3 (TRPM1), 21q22.3 (TRPM2), 9q21.12–q21.13 (TRPM3), 19q13.33 (TRPM4), 11p15.5 (TRPM5), 9q21.13 (TRPM6), 15q21.2 (TRPM7), 2q37.1 (TRPM8)
TRPA (Ankyrin)	TRPA1	8q21.11
TRPP (Polycystin)	PKD2 (TRPP2), PKD2L1 (TRPP3), PKD2L2	4q22.1 (PKD2), 10q24.31 (PKD2L1), 5q31.2 (PKD2L2)
TRPML (Mucolipin)	MCOLN1–3	19p13.2 (MCOLN1), 1p22.3 (MCOLN2, MCOLN3)

This classification underscores the evolutionary expansion of TRP channels in mammals, with subfamilies forming two broad groups: Group 1 (TRPC, TRPV, TRPM, TRPA) sharing closer ties to invertebrate prototypes like Drosophila TRP, and Group 2 (TRPP, TRPML) exhibiting distinct topologies and more distant relations.^[1]^[4]

Non-Mammalian and Variant Subfamilies

The transient receptor potential (TRP) channel family exhibits significant evolutionary diversity beyond mammalian subfamilies, with several variant subfamilies identified in non-mammalian organisms that provide insights into ancestral functions and comparative sensory biology. These include the TRPN, TRPS, TRPVL, and TRPY subfamilies, which collectively comprise fewer than 10 members across various non-vertebrate and lower vertebrate species, contrasting with the expanded repertoire in mammals.^[7] These variants often mediate mechanosensation, osmoregulation, and sensory transduction in environments distinct from those encountered by mammals, underscoring the family's adaptation to diverse ecological niches.^[8] The TRPN subfamily, characterized by its role in mechanosensation, is absent in mammals but present in 1-4 members in fish and amphibians, such as zebrafish and frogs. In zebrafish, the TRPN1 channel (orthologous to Drosophila nompC) is essential for mechanotransduction in sensory hair cells of the inner ear and lateral line, where it contributes to the detection of mechanical stimuli like water flow and sound vibrations by forming part of the transduction complex at stereocilia tips.^[9] This function highlights TRPN's conservation in aquatic vertebrates for environmental sensing, offering a model for understanding the evolution of auditory and vestibular systems.^[10] In insects, the TRPS subfamily serves sensory roles, with representatives like the Drosophila trpS channel implicated in olfactory processing and adaptation. Expressed in olfactory sensory neurons, TRPS channels facilitate calcium influx necessary for signal termination and adaptation to prolonged odor stimuli, enabling efficient chemosensory discrimination in dynamic environments.^[11] This subfamily diverged early in arthropod evolution, emphasizing TRP channels' foundational role in invertebrate olfaction before the expansion of more specialized subfamilies in vertebrates.^[12] The TRPVL subfamily, a long-variant form related to TRPV, appears in lower vertebrates and some invertebrates, such as amphibians and cnidarians, where it likely contributes to thermosensation and mechanosensitivity. In lower vertebrates, TRPVL channels exhibit extended N-terminal domains that may enhance sensitivity to environmental cues like temperature gradients in ectothermic species.^[7] Meanwhile, the TRPY subfamily in fungi, exemplified by TRPY1 in Saccharomyces cerevisiae, functions in osmotic regulation by acting as a mechanosensitive calcium channel activated by hypertonic stress and membrane stretch, helping maintain cellular turgor and ion homeostasis in response to osmotic challenges.^[13] These fungal channels represent an ancient branch of the TRP family, predating metazoan diversification and illustrating primordial osmoregulatory mechanisms.^[14] Overall, non-mammalian TRP variants reveal evolutionary divergence from the mammalian core, with conserved motifs supporting diverse sensory and homeostatic roles across kingdoms.^[7]

Molecular Structure

Core Architecture

Transient receptor potential (TRP) channels form tetrameric complexes, with each subunit consisting of six transmembrane segments (S1–S6) that span the lipid bilayer, a re-entrant pore loop between S5 and S6 that contributes to the ion conduction pathway, and intracellular N- and C-terminal domains that facilitate interactions with regulatory proteins and lipids.^[15] This overall topology mirrors that of voltage-gated ion channels, enabling the central pore to serve as a conduit for cation flux while the S1–S4 segments form a peripheral voltage-sensing-like domain in many subfamilies.^[1] The tetrameric assembly creates a symmetric structure with fourfold rotational symmetry around the pore axis, ensuring coordinated gating and permeation.^[16] Several conserved domains within the intracellular termini are critical for channel function and regulation across TRP channels. In the N-terminus, ankyrin repeats (ARs) are present in certain subfamilies, forming a modular protein-protein interaction scaffold that can bind ligands or other cellular components to modulate channel activity.^[17] Near the C-terminus, the TRP domain—a approximately 25-amino-acid sequence immediately following S6—contains a highly conserved EWKFAR motif (TRP box) that is implicated in gating and lipid interactions.^[3] Additionally, calmodulin-binding sites are commonly found in both N- and C-terminal regions, allowing calcium-dependent regulation through direct interaction with calmodulin to influence channel desensitization and trafficking.^[18] The pore architecture of TRP channels features a selectivity filter primarily formed by the pore loop, where key residues such as glycine or tyrosine create a narrow constriction that dictates ion selectivity.^[19] This filter confers non-selective cation permeability in most TRP channels, with a typical calcium-to-sodium permeability ratio (P_Ca/P_Na) of approximately 10:1, though this varies by subfamily and enables physiological calcium influx for signaling.^[20] The filter's flexibility allows adaptation to different cations, balancing permeation efficiency with selectivity.^[21] TRP channels assemble as either homotetramers or heterotetramers, with subunit interfaces stabilized by coiled-coil domains typically located in the C-terminal region, which promote oligomerization and ensure proper trafficking to the plasma membrane.^[22] These interactions allow for diverse functional complexes while maintaining the core tetrameric architecture essential for ion conduction.^[23]

Subfamily Variations and Groups

The transient receptor potential (TRP) channels exhibit notable structural variations across their subfamilies, primarily grouped by sequence homology into Group 1 (TRPC, TRPV, TRPM) and Group 2 (TRPA, TRPP, TRPML). These groups share a core tetrameric architecture with six transmembrane segments but diverge in domain organization, particularly in the intracellular N- and C-termini, leading to differences in overall channel length ranging from approximately 580 to 1100 amino acids. Sequence identity is generally low at 10-30% across subfamilies, though it increases to up to 50% within groups, reflecting evolutionary divergence while maintaining functional homology.^[1]^[24] In Group 1 subfamilies, the N-termini are typically longer and enriched with ankyrin repeats (ARs), which consist of 33-amino-acid motifs forming helical bundles that contribute to protein-protein interactions. The TRPC channels feature about 4 ARs in their N-terminal regions of roughly 300-400 amino acids, alongside a prominent TRP domain—a conserved ~25-amino-acid stretch immediately following the sixth transmembrane segment—that is larger and more extended compared to other groups. TRPV channels display 3-6 ARs in N-termini of 400-450 amino acids, with TRPV1 serving as a representative example possessing 6 ARs that form a structured domain essential for stability. TRPM channels, the largest subfamily, have exceptionally extended N-termini (732-1611 amino acids) with ARs present in some members like TRPM4, and they often include additional motifs such as enzyme domains (e.g., α-kinase in TRPM6/7 at the C-terminus). These subfamilies also commonly feature N-linked glycosylation sites in extracellular loops and lipid-binding pockets, such as those for phosphatidylinositol 4,5-bisphosphate (PIP2) in TRPC and TRPV channels, which involve positively charged residues in the C-terminal regions.^[1]^[24]^[25] Group 2 subfamilies show fewer ARs and distinct additional domains, emphasizing extracellular and regulatory elements over extensive intracellular scaffolds. TRPA channels have notably more ARs (14-18) in a prolonged N-terminus, contributing to their overall length of about 1100 amino acids, as seen in human TRPA1 with 16 ARs forming a dense helical array. TRPP channels lack ARs but include EF-hand motifs in the C-terminus for calcium binding, along with large extracellular polycystin domains between the first two transmembrane segments, resulting in lengths around 968 amino acids for TRPP2. TRPML channels are shorter (approximately 580 amino acids) and AR-free, featuring a lipase-like serine active site in the N-terminus and a polycystin-mucolipin domain in the luminal/extracellular region, as well as binding sites for phosphoinositides like PI(3,5)P2, though they share glycosylation patterns similar to Group 1. These variations in domain composition and length underscore the structural diversity that builds upon the conserved core architecture detailed elsewhere.^[1]^[24]^[26]

Biophysical Properties and Activation

Ion Permeability and Gating Mechanisms

Transient receptor potential (TRP) channels predominantly function as non-selective cation channels, permitting the influx of monovalent cations such as Na⁺ and K⁺, as well as divalent cations like Ca²⁺, though selectivity varies across subfamilies. For instance, TRPV5 and TRPV6 exhibit high Ca²⁺ selectivity akin to voltage-gated K⁺ channels, while channels like TRPV1, TRPA1, and most TRPC members allow permeation by a broader range of cations including large organic ions. This permeability profile contributes to their role in cellular depolarization and Ca²⁺ signaling. Single-channel conductances typically range from 20 to 100 pS, enabling significant ion flux under physiological conditions. At resting membrane potentials, many TRP channels display inward rectification, favoring cation entry over outward current, which enhances their sensitivity to depolarizing stimuli. The current-voltage relationship for TRP channels often follows an ohmic behavior described by the equation:

I = g (V - E_{\text{rev}})

where I is the ionic current, g is the single-channel conductance, V is the membrane potential, and E_{\text{rev}} is the reversal potential, typically near 0 mV for non-selective cation-permeable TRPs due to balanced Na⁺ and K⁺ permeabilities. Gating mechanisms of TRP channels are diverse and polymodal, integrating physical stimuli without reliance on specific ligands. Voltage-dependent gating is prominent in several subfamilies; for example, TRPM8 activates at cold temperatures below 28°C and is further modulated by depolarizing voltages, shifting its activation curve. Store-operated gating occurs in TRPC channels, triggered by endoplasmic reticulum Ca²⁺ depletion via interactions with STIM1, leading to sustained Ca²⁺ entry. Mechanical sensitivity is characteristic of TRPP channels, such as TRPP2, which respond to stretch or fluid shear forces through conformational changes in associated complexes. Many TRP channels undergo Ca²⁺-dependent desensitization, a feedback mechanism that limits prolonged activation and prevents Ca²⁺ overload. This inactivation involves calmodulin binding to intracellular domains, such as the C-terminus in TRPV1 and TRPM8, which stabilizes a closed state following Ca²⁺ influx. Structural elements like the ankyrin repeat domain may contribute to these dynamics, though detailed architecture is addressed elsewhere.

Modulators and Ligands

Transient receptor potential (TRP) channels are modulated by a diverse array of thermal stimuli, with specific subfamilies exhibiting sensitivity to distinct temperature ranges. The TRPV1 channel is activated by noxious heat above 43°C, a property that integrates with its responsiveness to chemical agonists. Similarly, TRPM8 responds to mild cold temperatures below 28°C, contributing to cool sensation detection. TRPA1 channels are sensitive to noxious cold below 17°C, highlighting their role in detecting extreme thermal cues. Chemical ligands further diversify TRP channel activation, encompassing both endogenous and exogenous compounds. Endogenous lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) regulate TRPC channels; PIP2 typically inhibits basal activity, while DAG directly activates TRPC3, TRPC6, and TRPC7 subfamilies independently of protein kinase C. Exogenous irritants like capsaicin activate TRPV1 by binding to a specific intracellular vanilloid pocket, mimicking heat-induced gating. Allyl isothiocyanate, the active component in mustard oil, covalently modifies cysteine residues in TRPA1 to elicit activation and pain signaling. Additionally, TRPV1 exhibits pH sensitivity, with protons (low pH) potentiating channel opening by protonating key histidine residues in the extracellular domain. Mechanical and osmotic stimuli also serve as modulators for select TRP channels. TRPV4 is activated by hypotonic cell swelling, which triggers calcium influx through osmotically induced conformational changes. TRPP2 responds to shear stress in vascular and renal environments, where fluid flow enhances channel activity to regulate endothelial calcium signaling. Allosteric modulators fine-tune TRP channel function through post-translational modifications and ligand binding. Phosphorylation by protein kinase C (PKC) at specific serine/threonine sites sensitizes channels like TRPV1 and TRPC3, enhancing their responsiveness to agonists. In the TRPM subfamily, intracellular ATP binds to nucleotide-binding domains in TRPM4 and TRPM5, inhibiting channel activity and preventing excessive cation influx during calcium signaling.

Physiological Functions

Sensory Transduction

Transient receptor potential (TRP) channels serve as key molecular sensors in sensory transduction, converting diverse environmental stimuli into electrical signals that initiate perceptual responses. These non-selective cation channels, permeable to calcium and sodium ions, are expressed in primary sensory neurons and specialized receptor cells, where they detect modalities such as temperature, chemical irritants, and mechanical forces. In sensory contexts, TRP activation leads to membrane depolarization, neurotransmitter release, and propagation of signals to the central nervous system, underpinning sensations like pain, cold, taste, and vision.^[1] In pain and temperature sensation, TRPV1 channels in nociceptive neurons act as primary detectors for noxious heat above 43°C and inflammatory pain, integrating signals from protons, lipids, and capsaicin-like compounds to trigger calcium influx and pain signaling.^[27] TRPM8 channels, conversely, mediate cool sensations below 25°C and menthol-evoked cold perception in cutaneous and visceral afferents, contributing to thermosensation and cold-induced analgesia.^[1] TRPA1 channels respond to pungent irritants, subfreezing cold, and inflammatory mediators, facilitating acute and chronic pain transmission through sodium and calcium entry in peptidergic nociceptors.^[27] Taste transduction relies on TRPM5 channels in type II taste receptor cells, where they amplify signals from G-protein-coupled receptors detecting sweet, bitter, and umami tastants via the phospholipase C pathway, leading to monovalent cation currents that depolarize cells and release ATP as a transmitter.^[28] This calcium-dependent mechanism is essential for gustatory perception, as TRPM5 knockout abolishes responses to these tastes without affecting sour or salty modalities.^[29] In vision, TRP and TRPL channels in Drosophila photoreceptors mediate phototransduction by opening in response to phospholipase C activation following rhodopsin stimulation, allowing calcium influx that sustains the light response and regulates adaptation in rhabdomeric microvilli.^[30] In mammals, TRPC1 and TRPC6 channels contribute to retinal signaling by modulating calcium entry in Müller glia, photoreceptors, and vascular endothelial cells, supporting light-dependent circuit tuning and vascular homeostasis in the retina.^[31] Other sensory functions include osmotic detection by TRPV4 channels in circumventricular organs and sensory neurons, which respond to hypotonicity and mechanical stretch to maintain fluid balance and evoke reflexive behaviors like drinking.^[32] TRPA1 also drives itch sensation, particularly in non-histaminergic pathways, by integrating pruritogenic signals from allergens, cytokines, and bile acids in cutaneous afferents to elicit scratching responses.^[33]

Cellular Signaling and Homeostasis

Transient receptor potential (TRP) channels play a pivotal role in intracellular calcium (Ca²⁺) signaling by facilitating store-operated Ca²⁺ entry (SOCE), a mechanism essential for refilling endoplasmic reticulum stores and sustaining downstream signaling cascades. TRPC1 and TRPC3 channels contribute to SOCE by forming heteromeric complexes with Orai1, where stromal interaction molecule 1 (STIM1) acts as the ER Ca²⁺ sensor to couple store depletion to channel activation at the plasma membrane.^[34] This interaction allows TRPC1/Orai1 assemblies to generate sustained Ca²⁺ influx distinct from the fast, highly selective CRAC currents mediated by Orai1 alone, thereby regulating gene expression and cellular processes like contraction in non-excitable cells.^[35] In various cell types, such as endothelial and epithelial cells, this SOCE pathway via TRPC1/3 ensures precise control of cytosolic Ca²⁺ levels for maintaining signaling fidelity.^[36] TRP channels also maintain elemental homeostasis critical for cellular viability and function. TRPM7, a unique channel with intrinsic kinase activity, regulates intracellular magnesium (Mg²⁺) homeostasis by permitting Mg²⁺ influx, which is vital for enzymatic reactions and cell survival; its deficiency leads to rapid Mg²⁺ depletion and growth arrest in cultured cells.^[37] At the organismal level, TRPM7 ensures systemic Mg²⁺ balance, as its knockout in mice causes embryonic lethality due to disrupted Mg²⁺ transport and cellular function.^[38] Similarly, TRPP2 forms part of the polycystin-1/2 complex in renal epithelial cells, where it conducts Ca²⁺ to support primary cilium integrity and tubular morphogenesis during kidney development, influencing cell polarity and differentiation.^[39] In cellular proliferation and migration, TRP channels modulate cytoskeletal dynamics and gene expression independently of sensory inputs. TRPC6 in vascular smooth muscle cells drives phenotypic switching from contractile to synthetic states by elevating intracellular Ca²⁺, which promotes proliferation and migration through activation of transcription factors like NFAT.^[40] TRPM4, a Ca²⁺-activated monovalent cation channel, regulates membrane potential in immune cells such as T lymphocytes and mast cells, facilitating depolarization that sustains Ca²⁺ signaling and cytokine production during activation.^[41] This depolarization by TRPM4 amplifies immune responses by enhancing Ca²⁺-dependent pathways without directly permeating divalent cations.^[42] A key signaling pathway involving TRP channels links Ca²⁺ influx to inflammatory regulation through activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). TRP-mediated Ca²⁺ entry, particularly via TRPC and TRPM subfamilies, triggers MAPK phosphorylation and NF-κB translocation, culminating in cytokine release such as IL-6 and TNF-α in non-immune cells like fibroblasts and epithelial cells.^[43] This pathway integrates environmental cues with transcriptional responses, ensuring coordinated cellular adaptation while avoiding excessive inflammation in homeostatic contexts.^[44]

Pathophysiological Roles

Involvement in Diseases

Dysregulation of transient receptor potential (TRP) channels contributes to a wide array of diseases through altered ion permeability, disrupted calcium signaling, and impaired cellular homeostasis. These channels are implicated in pathological processes across multiple organ systems, often via genetic mutations or environmental triggers that lead to gain- or loss-of-function phenotypes. For instance, loss-of-function mutations in TRP channels can result in channelopathies, while overexpression or hyperactivity frequently exacerbates inflammatory responses and tissue damage.^[45] In neurological disorders, TRP channels such as TRPA1 play a key role in conditions like migraine, where activation of TRPA1 on dural afferents by endogenous or exogenous irritants promotes neurogenic inflammation and pain signaling. Gain-of-function variants in TRPA1 have been linked to heightened sensitivity to migraine triggers, underscoring its contribution to episodic and chronic headaches. Similarly, in neurodegenerative contexts, TRP channel dysregulation affects neuronal excitability and survival, though specific mechanisms vary by subfamily.^[46]^[47] Cardiovascular diseases involve TRP channels in vascular tone regulation and remodeling; for example, TRPC6 hyperactivity contributes to hypertension by enhancing calcium influx in vascular smooth muscle cells, leading to vasoconstriction and elevated blood pressure. Overexpression of TRPC6 has been observed in both essential and pulmonary hypertension models, where it responds to mechanical stretch and receptor stimuli.^[48]^[49] Metabolic disorders, including diabetes, feature TRPM2 as a critical mediator, where its activation by oxidative stress and reactive oxygen species impairs insulin secretion and promotes β-cell dysfunction. In diabetic conditions, TRPM2 facilitates calcium-dependent pathways that exacerbate hyperglycemia and insulin resistance, linking channel activity to pancreatic pathophysiology.^[50]^[51] Key disease mechanisms include gain-of-function mutations that hyperactivate channels, leading to excessive calcium entry and cytotoxicity, and loss-of-function variants that disrupt essential signaling, as seen in channelopathies like mucolipidosis type IV caused by TRPML1 mutations, which impair lysosomal function and cause neurodegeneration. Overexpression of TRP channels, particularly in inflammatory states, amplifies immune responses and pain hypersensitivity through sustained cation influx. Genetic links are evident in conditions such as autosomal dominant polycystic kidney disease (ADPKD), where TRPP2 mutations disrupt polycystin signaling, promoting cyst formation and renal failure.^[52]^[53]^[54] Epidemiologically, TRP variants, especially in TRPA1, are associated with chronic pain syndromes, with rare variants identified in approximately 8% of patients exhibiting neuropathic or nociplastic pain in targeted cohorts. This highlights the channels' role in a notable subset of chronic pain cases, often involving sensory transduction dysregulation.^[55]

Role in Specific Disorders

Transient receptor potential (TRP) channels play critical roles in the pathogenesis of various disorders through dysregulated calcium signaling and cellular responses. In cancer, TRPC1 and TRPC6 channels facilitate tumor cell proliferation by mediating store-operated calcium entry, which activates downstream pathways essential for cell cycle progression. For instance, TRPC6 activation promotes G2/M phase transition and proliferation in gastric and breast cancer cells via sustained Ca²⁺ influx, enhancing AKT/β-catenin signaling and resistance to apoptosis. Similarly, TRPC1 couples with sodium-calcium exchangers to drive Ca²⁺-dependent proliferation in Helicobacter pylori-associated gastric cancer. In prostate cancer, TRPM8 expression is upregulated in early-stage tumors but downregulated in metastatic lesions, where its loss correlates with increased invasiveness and dissemination; overexpression of TRPM8 inhibits migration and adhesion by sequestering Rap1A in an inactive state, thereby limiting metastasis in orthotopic xenograft models. Inflammatory disorders involve TRP channels in amplifying cytokine-mediated responses and tissue damage. TRPV1 activation in rheumatoid arthritis synovial fibroblasts enhances the release of pro-inflammatory cytokines such as IL-6 and IL-8, triggered by neuropeptides like substance P and calcitonin gene-related peptide, which sensitize the channel and exacerbate joint inflammation. In osteoarthritis, TRPV1 contributes to cytokine production in synovial tissues, promoting macrophage polarization and disease progression through Ca²⁺/CaMKII/Nrf2 pathway modulation. For asthma, TRPA1 channels mediate bronchoconstriction by responding to inhaled irritants and allergens, leading to airway hyperresponsiveness; antagonism of TRPA1 reduces ovalbumin-induced early and late asthmatic responses in vivo and reverses histamine-evoked narrowing ex vivo. Chronic pain conditions highlight TRP channel sensitization as a key mechanism for hyperalgesia. In neuropathic pain, TRPV1 undergoes sensitization in primary sensory neurons, amplifying thermal and mechanical hypersensitivity through inflammatory mediators like TNF-α, which upregulates channel expression and promotes mechanical allodynia via spinal cord mechanisms. Central terminal sensitization of TRPV1 by descending serotonergic facilitation further sustains chronic pain states. Mutations in TRPM3, particularly gain-of-function variants, underlie developmental pain disorders such as intellectual disability with epilepsy and severe pain hypersensitivity, where altered channel activity disrupts neurodevelopment and enhances nociceptive signaling. Organ-specific pathologies demonstrate TRP channels' involvement in compartmentalized dysfunction. TRPC6 drives pulmonary edema by increasing endothelial permeability through Ca²⁺ influx in response to ischemia-reperfusion or endotoxin challenges, a mechanism implicated in acute respiratory distress syndrome; in COVID-19, TRPC6 expression is altered in infected lung tissues, potentially exacerbating inflammation and edema, though pharmacological inhibition did not improve outcomes in clinical trials. TRPML1 mutations cause mucolipidosis type IV, a lysosomal storage disease characterized by neurodegeneration and corneal clouding, due to impaired lysosomal Ca²⁺ release and lipid trafficking, leading to accumulation of undegraded substrates. In Alzheimer's disease, TRPM2 channels in microglia promote neuroinflammation by facilitating Ca²⁺-dependent cytokine release and oxidative stress; recent studies show that TRPM2 deficiency attenuates amyloid-β-induced inflammation and cognitive deficits via enhanced autophagy and AMPK/mTOR pathway activation.

Therapeutic Potential

Channel Modulators and Drugs

Transient receptor potential (TRP) channels are modulated by a variety of pharmacological agents, including synthetic compounds and natural products, which act as agonists, antagonists, or allosteric regulators to influence channel gating and ion permeability. These modulators typically bind to specific sites on the channel proteins, altering their conformational states and sensitivity to stimuli such as temperature or ligands. Agonists activate TRP channels to promote cation influx, while antagonists inhibit this process, often through competitive or pore-blocking mechanisms. Such tools are essential for dissecting TRP function in cellular contexts. Prominent agonists include capsaicin, which selectively activates TRPV1 by binding to its intracellular vanilloid-binding domain, inducing channel opening and calcium influx at concentrations around 1 μM. Icilin serves as a potent super-agonist for TRPM8, eliciting cooling-like responses by stabilizing the open state of the channel with higher efficacy than menthol, effective at nanomolar levels. Carvacrol, a monoterpenoid found in oregano, acts as an agonist for TRPV3, directly interacting with the S2-S3 linker region to facilitate channel activation and thermosensitivity at low micromolar concentrations. Antagonists provide specificity for blocking TRP activity; ruthenium red is a broad-spectrum pore blocker that inhibits multiple TRPV and TRPA channels by binding within the selectivity filter, preventing ion permeation at sub-micromolar doses. HC-030031 functions as a selective TRPA1 antagonist, suppressing allyl isothiocyanate-induced currents by allosteric modulation, with an IC50 of approximately 6 μM. For TRPC channels, SKF-96365 inhibits receptor-mediated calcium entry by targeting TRPC isoforms, blocking store-operated currents at 10-50 μM without affecting other major calcium channels. Natural compounds also modulate TRP channels; for instance, gingerol from ginger activates TRPV1 similarly to capsaicin but with milder potency, binding to the vanilloid site and enhancing channel sensitivity through hydrogen bonding interactions. Additionally, kinase inhibitors influence TRP function via phosphorylation-dependent regulation; Src family kinase inhibitors like PP1 reduce tyrosine phosphorylation of TRPV4, diminishing channel activity under hypotonic conditions, while protein kinase C inhibitors prevent serine phosphorylation of TRPV4 at S824, modulating its gating properties. Developing selective TRP modulators faces challenges due to structural homologies among family members, leading to off-target effects that complicate specificity in experimental and therapeutic contexts. Recent advances as of 2025 have focused on selective TRPM2 inhibitors, with novel scaffolds like adamantyl derivatives emerging as potent blockers (IC50 <1 μM) that minimize hERG channel interference and exhibit improved selectivity over broad-spectrum agents.^[56]

Clinical Applications and Challenges

Transient receptor potential (TRP) channel modulators have advanced into clinical applications, particularly for pain and respiratory conditions. TRPV1 antagonists, such as the modality-selective compound NEO6860, showed a numerical trend toward analgesic efficacy in patients with osteoarthritis knee pain during a randomized, controlled phase II proof-of-concept trial, with reductions in pain scores (though not statistically significant compared to placebo) and without inducing the hyperthermia or heat insensitivity seen with non-selective TRPV1 blockers.^[57] Similarly, TRPA1 inhibitors like GDC-6599 are under evaluation in phase II trials for refractory chronic cough associated with asthma, showing potential to suppress neurogenic inflammation and airway hypersensitivity by targeting TRPA1-mediated cough reflexes. Emerging therapeutic strategies leverage other TRP subtypes for organ-specific disorders. TRPC6 inhibitors, including BI 764198, are being tested in phase II trials for focal segmental glomerulosclerosis, a kidney disease where TRPC6 hyperactivity contributes to podocyte injury and proteinuria progression, with early data indicating potential renoprotective effects through reduced proteinuria.^[58] For overactive bladder, research has associated TRPM8 involvement in cold-induced detrusor activity with symptom relief via modulation of sensory pathways; the FDA-approved beta-3 adrenergic agonist mirabegron (approved 2012) enhances bladder relaxation and may indirectly involve such pathways.^[59] In 2025, positive phase III trial results for the TRPM8 agonist acoltremon (AR-15512) in the COMET-2 and COMET-3 studies led to FDA approval for dry eye disease, demonstrating rapid increases in natural tear production and symptom improvement in over 930 patients.^[60] Clinical translation of TRP modulators faces significant challenges, including on-target adverse effects and pharmacological limitations. Blockade of TRPV1 often induces hyperthermia by disrupting thermoregulatory circuits, as observed in early clinical trials where antagonists elevated core body temperature through impaired heat dissipation via peripheral nociceptors.^[61] Poor selectivity remains a barrier, with many modulators exhibiting off-target interactions across TRP family members or other ion channels, leading to unintended physiological disruptions and complicating dose optimization.^[62] Cardiovascular risks, such as arrhythmias or hypertension exacerbation, have also emerged as concerns with certain TRP inhibitors, particularly those affecting TRPC or TRPM4 channels involved in cardiac conduction.^[63] Looking ahead, gene therapy approaches hold promise for TRP-related genetic disorders, such as mucolipidosis type IV caused by TRPML1 mutations, where adeno-associated virus-mediated delivery of functional TRPML1 has shown preclinical efficacy in restoring lysosomal function and reducing neurodegeneration in animal models.^[64] These strategies aim to address root causes but must navigate delivery challenges and long-term safety profiles to reach clinical viability.

Research Advances

Structural Biology Insights

The landmark determination of the rat TRPV1 ion channel structure using cryo-electron microscopy (cryo-EM) in 2013 achieved a resolution of 3.4 Å, providing the first near-atomic view of a mammalian TRP channel and revealing its tetrameric assembly with transmembrane helices analogous to voltage-gated ion channels.^[65] Building on this, the 2020s saw substantial progress with high-resolution structures of other TRP subtypes, including human TRPC6 resolved at 2.9 Å in a calcium-bound state in 2022, which illuminated its intracellular calcium-binding sites and pore domain dynamics.^[66] Similarly, cryo-EM structures of human TRPM4 in various ligand-bound states reached resolutions around 3.1–3.4 Å by 2024, capturing its nucleotide-sensitive gating mechanisms.^[67] These milestones have collectively mapped the core architectural features across TRP subfamilies, emphasizing their modular domains for sensory and regulatory functions. Cryo-EM remains the dominant technique for obtaining near-atomic models of TRP channels, often embedded in lipid nanodiscs to mimic native membranes and capture functional states under diverse conditions such as ligand binding or temperature shifts.^[15] This approach has enabled the resolution of flexible regions like intracellular domains that were elusive in earlier X-ray crystallography efforts. Complementing experimental structures, AlphaFold predictions have proven valuable for modeling disease-associated variants in TRP channels, such as mutations altering gating in TRPV1 or TRPC6, by forecasting structural perturbations with high accuracy when integrated with cryo-EM data.^[68] For instance, AlphaFold2 has aided in simulating variant-induced changes in heteromeric assemblies, bridging gaps in experimental datasets for underrepresented isoforms. Structural insights from these models highlight extensive lipid-binding sites that fine-tune TRP channel activity, with a comprehensive 2024 analysis identifying 40 distinct sites across subfamilies, including those in the voltage-sensor-like domain and pore helix for phospholipids like PIP2.^[69] These sites often mediate allosteric gating transitions, as evidenced by cryo-EM snapshots of TRPV1 showing concerted movements between the S1–S4 linker and selectivity filter upon capsaicin or heat activation, propagating from peripheral lipid interactions to central pore dilation.^[70] In TRPC6, lipid occupancy at intersubunit clefts stabilizes the closed state, with displacement triggering calcium-dependent opening, underscoring a conserved allosteric network.^[66] A pivotal advance involves the elucidation of heterotetramer interfaces in TRP channels, particularly in canonical subfamilies like TRPC, where 2024 cryo-EM structures of TRPC1/TRPC4 heteromers at 3.2 Å resolution exposed asymmetric subunit arrangements and lipid-filled crevices at junctions that dictate assembly specificity and conductance properties.^[71] These interfaces reveal novel pockets for modulator binding, enhancing drug design prospects; for example, the TRPV1 capsaicin-binding site at the cytoplasmic gate, refined in multiple cryo-EM states, demonstrates how agonists exploit helical bundle distortions for selective activation.^[65] Such details inform targeted interventions by pinpointing allosteric hotspots without disrupting heteromeric stability. In late 2025, a cryo-EM structure of TRPM4 in an open state bound to calcium and PI(4,5)P2 at high resolution further clarified lipid modulation of gating transitions.^[72]

Emerging Therapeutic Targets

Transient receptor potential canonical 6 (TRPC6) channels have emerged as promising targets in vascular disorders, particularly hypertension, where their inhibition shows preclinical potential for mitigating endothelial dysfunction and vascular remodeling. Recent genetic studies indicate that reduced TRPC6 expression is associated with lower risks of heart failure and stroke, supporting its role in hypertensive pathophysiology. Preclinical investigations in 2024 demonstrated that selective TRPC6 inhibitors, such as PCC0208057, attenuate vascular smooth muscle proliferation and improve endothelial barrier function in hypertensive models, paving the way for novel antihypertensive therapies.^[73]^[74]^[75] Similarly, TRPV4 channels contribute to vascular permeability in edema formation, with antagonists exhibiting therapeutic efficacy in reducing fluid accumulation in preclinical models of pulmonary and cerebral edema.^[76] In ocular biology, TRPM8 channel modulators represent an advancing frontier for dry eye disease treatment, with 2025 clinical trials demonstrating significant symptom relief. The TRPM8 agonist acoltremon (0.003% ophthalmic solution), approved by the FDA in May 2025, restored natural tear production and reduced ocular discomfort in phase 3 studies, marking the first TRPM8-targeted therapy for this condition.^[77]^[78] Beyond the eye, TRP channels influence hair follicle cycling, as evidenced by 2025 ex vivo studies on human hair follicles showing that TRPV3 and TRPV4 activation promotes anagen phase progression and keratinocyte proliferation, suggesting potential applications in alopecia treatments.^[79] Additionally, TRPV1 channels are implicated in dysphagia management, with a 2023 review highlighting their role in enhancing swallow reflex safety through sensory stimulation in oropharyngeal dysphagia patients.^[80] TRP channel expression profiles also hold prognostic value as biomarkers in cancer, particularly TRPM8 in prostate cancer, where 2024 analyses confirmed its overexpression correlates with tumor progression and poor outcomes, enabling risk stratification in clinical settings.^[81] Current research gaps include the absence of TRPN-like mechanosensors in mammals, underscoring the need for identifying analogous channels to fully elucidate mammalian mechanotransduction pathways. Furthermore, recent studies including 2025 investigations emphasize TRPM2 as a key target in neurodegeneration, with its inhibition reducing oxidative stress and neuronal loss in models of Parkinson's disease and traumatic brain injury, indicating untapped therapeutic potential in these disorders.^[82]^[83]

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https://pubmed.ncbi.nlm.nih.gov/40571589/